Delta 4&#39;,alpha-analogs of lincomycin

ABSTRACT

COMPOUNDS OF THE FORMULA:   6-(CH3-CH(-HALO)-CH(-NH-AC)-),3,4,5-TRI(HO-),2-(R-S-)-   TETRAHYDROPYRAN   WHERE AC IS THE ACYL OF AN ACID OF THE FORMULA   2-(HOOC-),4-(R&#39;&#39;=)PYRROLIDINE, OR 1-(ALKYL-),2-(HOOC-),   4-(R&#39;&#39;=)PYRROLIDINE   ARE PREPARED BY REPLACING BY CHLORINE OR BROMINE THE 7-HYDROXY OF A COMPOUND OF THE FORMULA:   6-(CH3-CH(-OH)-CH(-NH-AC)-),3,4,5-TRI(HO-),2-(R-S-)TETRA-   HYDROPYRAN

United States Patent Ofi ice 3,726,858 Patented Apr. 10, 1973 3,726,858A*'--ANALOGS F LINCOMYCIN Robert D. Birkenmeyer, Comstock Township,Kalamazoo County, and Fred Kagan, Kalamazoo, Mich., assignors to TheUpjohn Company, Kalamazoo, Mich. No Drawing. Continuation-impart ofapplication Ser. No. 864,893, Oct. 8, 1969, now Patent No. 3,574,186,which is a continuation-in-part of application Ser. No. 696,513, Jan. 9,1968, which is a continuation-in-part of application Ser. No. 511,288,Dec. 1, 1965, which in turn is a continuation-in-part of applicationSer. No. 431,184, Feb. 8, 1965, all now abandoned. Said application Ser.No. 864,893 being a continuation-in-part of applications Ser. No.587,662, Oct. 19, 1966, now abandoned, and Ser. No. 696,518, Jan. 9,1968, now Patent No. 3,496,- 163. This application Sept. 3, 1970, Ser.No. 69,436 Int. Cl. C07c 47/18 U.S. Cl. 260210 R 10 Claims ABSTRACT OFTHE DISCLOSURE Compounds of the formula:

- Halo where Ac is the acyl of an acid of the formula Alkyl are preparedby replacing by chlorine or bromine the 7-hydroxy of a. compound of theformula:

011 AcNH- ar- CROSS REFERENCES TO RELATED APPLICATION No. 587,662, filedOct. 19, 1966, now abandoned, and

Ser. No. 696,518, filed Jan. 9, 1968, now U.S. Pat. 3,496,163.

BRIEF SUMMARY OF INVENTION This invention relates to novel compounds ofthe formula sift,

wherein Halo is chlorine or bromine; R is alkyl of not more than 20carbon atoms, advantageously not more than 8 carbon atoms, cycloalkyl offrom 3 to not more than 8 carbon atoms, and aralkyl of not more than 12carbon atoms, advantageously not more than 8 carbon atoms; and Ac is theacyl radical of a 4-substituted-L-Z-pyrrolidinecarboxylic acid of theformula Alkyl wherein R is alkylidene of not more than 20 carbon atoms(including methylene), advanageously not more than 8 carbon atoms,cycloalkylidene of from 3 to not more than 8 carbon atoms, andaralkylidene of not more than 12 carbon atoms, advantageously not morethan 8 carbon atoms; and alkyl conains no more than 20 carbon atoms,advantageously not more than 2 carbon atoms. Ac can also be an acylradical of-a 4-substitued-L-Z-pyrrolidinecarboxylic acid of the formula:

of the latter are tertiary-butoxycarbonyl; benzyloxycarbonyl groups ofthe formula:

wherein X is hydrogen, nitro, methoxy, chloro, or bromo, for example,carbobenzoxy, p-nitrocarbobenzoxy, pbromoand p-chlorocarbobenzoxy; andphenyloxycarbonyl groups of the formula:

wherein X is hydrogen, allyl, or alkyl of not more than 4 carbon atoms,such as phenyloxycarbonyl, p-tolyloxycarbonyl, p-ethylphenyloxycarbonyl,and p-allylphenyloxycarbonyl and the like.

Examples of alkyl of not more than 20 carbon atoms, (R and alkyl) aremethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl,decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl,heptadecyl, octadecyl, nonadecyl, and eicosyl and the isomeric formsthereof, examples of cycloalkyl are cyclopropyl, cyclo- DETAILEDDESCRIPTION The compounds of Formula I were Halo is chlorine can beprepared by replacing by chlorine, the 7-hydroxy of a compound of theformula:

AONH- wherein Ac is the acyl of the acid B, C, or D. The replacement iseifected by (l) mixing the starting compound of Formula II with thionylchloride, (2) heating with thionyl chloride, and (3) solvolysis. Thisprocess is described and claimed in our parent application Ser. No.864,893.

Thionyl chloride without heating converts the compounds of Formula II toa 3,4-O-cyclic sulfite of the formula:

Heating with thionyl chloride converts compounds of Formulas II and IIIto a 3,4-O-cyclic sulfite of the formula:

(III) AcNH- OH (IV) and a bis-sulfite of the formula:

I/ SR 4 Solvolysis converts compounds of Formulas IV and V to a7-chloro-7-deoxylincomycin of the formula.

AeNH- wherein Ac is the acyl of the acid A.

The replacement where Halo is chlorine or bromine can also be effectedby means of a Rydon reagent. This process is described and claimed inU.S. Pat. 3,496,163. In the process triphenylphosphine is reacted withchlorine or bromine to form triphenylphosphinedihalide which is reactedwith the starting compound of Formula II in a suitable solvent such ascarbon tetrachloride, chloroform, methylene chloride, ethylene chloride,ether, or benzene. Alternatively a mixture of triphenylphosphine andcarbon tetrachloride or carbon tetrabromide can be used as the Rydonreagent, using an excess of the carbon tetrahalide as solvent or anothersolvent as above.

The Rydon reagent process can also be applied to compounds of FormulaIII to produce compounds of Formula IV.

Alternatively the compounds of Formula I can be prepared by acylating acompound of the formula:

(VII) where R and Halo are as given above .with an acid of Formula B, C,or D. Compounds of Formula VI are prepared by the process of the parentapplication Ser. No. 864,893 or the process of U.S. Pat. 3,496,163. Theacylation can be effected in any suitable manner for example byconverting the acid to the mixed anhydride with isobutyl chloroformateas in U.S. Pats. 3,380,992 and 3,496,163.

The starting compounds of Formula II wherein Ac is acyl are prepared byacylating a compound of the formula:

HO 0 i OH ll R 0H (VI wherein R is as given above, with a4-substituted-L-2- pyrrolidinecarboxylic acid of Formulas B, C, or D.This acylation and like acylations referred to herein can also be aeffected by procedures already Well known in the art.

The starting acid of Formula A can be prepared by reacting a 4-oxocompound of the formula:

wherein Z is a protective group which is removable by which onsolvolysis is converted to the starting acid of Formula A.

If desired, the starting compounds of Formula II can be acylated withacids of Formula C or D to form compounds 11C and 11D respectively.Compound 11C can then be converted to compound 11D by treatment with aWittig reagent. Starting acids of Formula B are obtained by treating anacid of Formula D with hydrogen bromide in acetic acid to remove the Zgroup and then replacing the N-hydrogen with an Alkyl group byalkylation with an alkyl iodide, for example, methyl or ethyl iodide.Compounds of Formula 11D are converted to compounds of Formula IIA andthen to compounds of Formula 118 by the same process.

Also where Z is removable by hydrolysis, for example, when Z istertiary-butoxycarbony], compounds of Formulas I and II where Ac is theacyl of the acid of Formula D are converted by hydrolysis to compoundsof Formulas I and II wherein Ac is the acyl of acid A.

Any and all of the compounds described in U.S. Pat. 3,380,992 can beconverted to the corresponding A 7-chloro-7-deoxy and A'--1-dimethyl-7-chloro-7-deoxylincomycins by the process of theinvention.

A particularly effective process is to acylate a compound of Formula V1with an acid of Formula D where Z is carbo-t-butoxy.

This acylation step can also be elfected by any suitable acylationprocedures well known in the art. A suitable such process is to reactthe l-(carbo-t-butoxy)-4-alkylidene-L-Z-pyrrolidenecarboxylic acid withisobutyl chloroformate in a suitable solvent, for example, acetonitrile,in the presence of an acid binding agent, for example, triethylamine,and reacting the alkyl 7-halo-7-deoxy-m-thiolincosaminide (Formula VI)with the mixed anhydride thus formed.

The isobutyl chloroformate advantageously is added to a cooled solutionof the acid and acid binding agent and the aminosugar then added.Advantageously a temperature of about 5 C. is maintained throughout thereaction but higher or lower temperatures, say from about --20 to about25 C. can be used. The alkyl N-(1'-(carbo-tbutoxy)-4'-alkylidene-L-2-pyrrolidinecarhonyl) 7 halo-7-deoxy-a-thiolincosaminide thus formed can be isolated in the usualmanner. It is not necessary, however, that it be obtained in a pureform. It is desirable, however, to remove the bulk of the other reactionproducts and materials, for example, by evaporation to dryness andextraction of the residue with a solvent for the alkyl N-(1'-(carbo-t-butoxy) 4' alkylidene-L-2'-pyrrolidenecarbonyl)-7halo-7-deoxy athiolincosaminide, for example, methylene chloride.

The selective solvolysis step is advantageously accomplished by acidmethanolysis. Thus, by subjecting the alkyl N-(l' (carbo-butoxy) 4'alkylidene-L-Z-pyrrolidinecarbonyl) 7 halo-7-deoxy-a-thiolincosaminideto the acid catalyzed solvolptic action of methanol the carbo-tbutoxygroup is cleaved with little or no cleavage of the amide linkage. Theacid methanolysis can be effected simply by dissolving the alkylN-(1-(carbo-t-butoxy)-4'- alkylidene-L-2'-pyrrolidinecarbonyl) 7 halo 7deoxya-thiolincosaminide in methanol which is acidified withhydrochloric acid. If desired, gentle heating, for example, on a steambath, can be used to accelerate the cleavage. The alkylN-(4'-alky1idene-L-2'-pyrrolidinecarbonyl) 7-halo-7-deoxy-a-thiolincosaminide (Formula 1A) can be isolated in theusual manner suitable by solvent extractions and crystallization.

It is sometimes desirable to start the process with l-carbobenzoxy 4alkylidene L 2 pyrrolidinecarboxylic as this material is readilyavailable from l-carbobenzoxy- 4-oxo-L-2-pyrrolidinecarboxylic acid bythe procedures described in US. Pat. 3,380,992.

The l-carbobenzoxy group is cleaved by acid cleavage so that the A--unsaturation is preserved and the resulting4-alkylidene-L-Z-pyrrolidinecarboxylic acid is N-acylated with anN-carbo-t-butoxylating agent tol-(carbo-tbutoxy)-4-alkylidene-L-Z-pyrrolidinecarboxylic acid.

The acid cleavage can be effected advantageously by dissolving the1-carbobenzoxy-4-alkylidene-2-pyrrolidinecarboxylic acid in 30% hydrogenbromide-acetic (glacial acetic acid substantially saturated withhydrogen bromide). The cleavage takes place at room temperature (25 C.).The 4-alkylidene-L-2-pyrrolidinecarboxylic acid thus liberated can beseparated by the usual method such as solvent extraction andcrystallization.

Acylation of the 4-alkylidene-L-Z-pyrrolidinecarboxylic acid thus formedwith tertiary-butoxy-carbonic acid can be effected with any suitableacylating agent. Advantageously t-butoxy-carbonylazide is used. Thereaction can be effected in 50% aqueous dioxane, or like solvent,advantageously in the presence of a weak base such as magnesium oxide.The reaction proceeds at room temperature (25 C.) but mild heating up toabout 60 C. can be used if desired. Thel-(carbo-t-butoxy)-4-alkylidene-L-Z-pyrrolidinecarboxylic acid thusobtained can be isolated by the usual procedures. It is not necessary tothe process, however, that it be recovered in a pure state as thesubsequent steps can be performed on a crude product. Ordinarily, itwill be sufiicient to remove the bulk of the extraneous material byextraction in a solvent such as ethyl acetate and evaporation of thesolvent.

The compounds of the invention (Formula I) exist either in theprotonated or non-protonated forms according to the pH of theenvironment. When the protonated form is intended, the compound isqualified as an acidaddition salt and when the non-protonated form isintended it is qualified as the free base. The free bases can beconverted to stable acid-addition salts by neutralizing the free basewith the appropriate acid to below about pH 7.0, and advantageously toabout pH 2 to pH 6. Suitable acids for this purpose includehydrochloric, sulfuric, phosphoric, thiocyanic, fiuorosilicic,hexafiuoroarsenic, hexafiuorophosphoric, acetic, succinic, citric,lactic, maleic, fumaric, pamoic, cholie palimitic mucic, camphoric,glutaric, glycolic, phthalic, tartaric, lauric stearic, salicylic,S-phenylsalicylic, 5-phenylsalicylic, 3-methylglutaric,orthosulfobenzoic, cyclopentanepropionic, 1,2-cyclohexanedlcarboxylic,4-cyclohexanecarboxylic, octadecenylsuc- 611116, octenylsuccinic,methanesulfonic, benzenesulfonic, helianthic, Reineckes,dimethyldithiocarbamic, cyclohexylsulfamic, hexadecylsulfamic,octadecylsulfamic, sorbic, monochloroacetic, undecylenic,4'-hydroxyazobenzene-4- sulfonic, octyldecylsulfuric, pricric, benzoic,cinnamic, and like acids.

The acid-addition salts can be used for the same purposes as the freebase or they can be employed to upgrade the same. For example, the freebase can be converted to an insoluble salt, such as the picrate, whichcan be subjected to purification procedures, for example, solventextractions and washings, chromatography, fractional liquid-liquidextractions, and crystallization and then used to regenerate the freebase form by treatment with alkali or to make a different salt bymetathesis. Or the free base can be converted to a water-soluble salt,such as the hydrochloride or sulfate and the aqueous solution of thesalt extracted with various water-immiscible solvents beforeregenerating the free base form by treatment of the thus-extracted acidsoluton or converted to another salt by metathesis. The free bases canbe used as a buffer or as an antacid. The compounds of Formula I alsoreact with isocyanates to form urethanes and can be used to modifypolyurethane resins. The long chain compounds, i.e., where R is alkyl offrom 8 carbon atoms up, having surface active properties can be used aswetting and emulsifying agents. The thiocyanic acid addition salt whencondensed with formaldehyde forms resinous material useful as picklinginhibitors according to US. Pats. 2,425,320 and 2,606,155. The freebases also make good vehicles for toxic acids. For example, thefiuosilicic acid addition salts are useful as mothproofing agentsaccording to US. Pats. 1,915,334 and 2,075,359 and the hexafluoroarsenicacid addition salts are useful as parasiticides according to U.S. Pats.3,122,536 and 3,122,552.

Methyl N (4 propylidene-L-2-pyrrolidinecarbonyl)-7-halo-7-deoxy-a-thiolincosaminide and its close analogues, i.e., whereR contains not more than 8 carbon atoms and R and alkyl are methyl orethyl, have antibacterial properties similar to lincomycin and can beused for the same purposes as lincornycin. The other analogues andisomers also show anti-bacterial properties and can likewise be used totreat infections in animals due to Gram positive organisms.

The following examples are illustrative of the process and products ofthe present invention but are not to be construed as limiting. The partsand percentages are by weight and the solvent ratios are by volumeunless otherwise specified.

EXAMPLE 1 A 1 -demethyl-7 (S -chloro-7-deoxylincomycin hydrochlorideA-l.4-propylidene-L-2-pyrrolidinecarboxylic acid Cbx III N W I COOH CHc0011 CH 1 32115 A quantity of 18.9 g. of1-barbobenzoxy-4-propylidene-L- 2-pyrrolidinecarboxylic acid isdissolved in 9 ml. of 30% hydrogen bromide-acetic acid. After 35 min.the reaction mixture is diluted with 1400 ml. of anhydrous ether. Afterstanding for 3 hrs. the ether is decanted and 1 liter of fresh etheradded. After stirring for 3 hrs. 12.3 g. of4-propylidene-L-2-pyrrolidinecarboxylic acid hydrobromide is recoveredby filtration. This product is dissolved in 30 ml. of water and passedover a column of 135 g. of cage resin. There is recovered 7.7 g. of4-propylidene-L-2 pyrrolidinecarboxylic acid by lyophilization of theeffluent. This material is crystallized from methanol-ethyl acetate togive 3.0 g. of 4-propylidene-L-2-pyrrolidinecarboxylic acid, M.P. 202208C.

A portion on recrystallization from the same solvent affords ananalytical sample, M.P. 220-228 C. dec., [aJ 51 (H O).

Analysis.- Calcd. for C H NO (percent): C, 61.91; H, 8.44; N, 9.03.Found (percent): C, 61.78; H, 8.67; N, 8.96.

Cage resins are ion retardation resins obtained by polymerizing acrylicacid in strongly basic quaternary ammonium cross-linked polystyreneanion exchange resin. Kirk-Othner, Encyclopedia of Chemical Technology,Vol. 11, p. 876, 2d ed., for example Retardation 11 A8 and Bio-Rad A61resins.

B-1.-1-(carbo-t-butoxy) 4 propylidene-L-Z-pyrrolidinecarboxylic acid 0001311) H N ,aN U

2 COOH C O OH 1101120113 HCHZCHs A mixture of 4.0 g. of4-propy1idene-L-2-pyrrolidinecarboxylic acid, 2.07 g. of MgO, and 7.37g. of t-butoxycarbonylazide in ml. of 50% aq. dioxane is stirred atambient temperature for 96 hrs. The mixture is diluted with ml. of waterand then extracted three times with ethyl acetate. The cooled aqueoussolution is acidified to pH 5 by the addition of 10% citric acidsolution. On extraction with three portions of ethyl acetate followed bydrying and evaporation of the solution 3.6 g. (54.9%) of crude 1(carbo-t-butoxy)-4-propylidene-L-pyrrolidinecarboxylic acid is obtainedas an oily residue. This material is used directly in the next step.

C1.-Methyl 7 deoxy 7(S)-chloro-a-thio1incosaminide.

C1a.To a suspension of 197.2 g. of triphenylphosphine in 1.5 l. ofanhydrous acetonitrile is added 52.5 g. p

of chlorine. With stirring, 18.75 g. of methyl a-thiolincosaminide (US.Pat. 3,179,565) is added. After 2.5 hrs. at ambient temperature, 50 ml.of methanol is added. The mixture is concentrated to a thick syrup. Theconcentrate is diluted with methylene chloride and extracted three timeswith water. The aqueous extracts are washed twice with methylenechloride. The extracts are made alkaline with sodium hydroxide andextracted repeatedly with methylene chloride. The organic extract isdried and evaporated under vacuum. The residue is chromatographed over1.1 kg. of silica gel using chloroform-methanol (4:1) for elution. Themajor fraction selected on the basis of its TLC (thin layerchromatography) profile weighs 4.4 g. Recrystallization frommethanol-water affords 2.73 g. of methyl7(S)chloro-7-deoxy-u-thiolincosaminide, M.P. 178-181 C.

Analysis.-Calcd. for C H ClNO S (percent): C, 39.77; H, 6.67; N, 5.16;S, 11.80; Cl, 13.05. Found (percent): C, 39.91; H, 7.02; N, 5.57; S,11.99; Cl, 13.33.

C1b.A mixture of 1.0 g. of methyl u-thlOllIlCOS- aminide, 3.0 g. oftriphenylphosphine, 10 ml. of carbon tetrachloride, and 100 ml. ofacetonitrile is heated at reflux for 3 hrs. The reaction mixture isevaporated to dryness under vacuum and the residue purified bychromatography over 500 g. of silica gel using a solvent system composedof chloroform and methanol (4:1). The product fractions (as determinedby TLC) are collected, combined, and evaporated to a white solid. Onrecrystallization from ethanol, there is obtained 250 mg. (23.3%)

of crystals of methyl 7(S)-chloro-7-deoxy-a-thiolincosaminide, M.P.169172 C. having a LR. identical with the product of Part C-la.

D1.Methyl N (1' (c'arbo-t-butoxy)-4'-propylidene L 2'pyrrolidinecarbonyl)-7 deoxy-7(S)-chloro a-thiolincosaminide To asolution of 3.6 g. of 1-(carbo-t-butoxy)-4-propylilene-L-Z-pyrrolidinecarboxylic acid and 1.96 ml. of triethylamine in 90ml. of acetonitrile cooled to 50 C. is added 1.8 ml. of i-butylchloroformate. After 30 min. a solution of 3.82 g. of methyl7(S)-chloro-7-deoxy-athiolincosaminide in 40 ml. of water and 40 ml. ofacetone is added. After stirring for 4 hrs., the acetonitrile isdistilled under vacuum and the product recovered by extraction withmethylene chloride. After drying and evaporation of the solvent methylN-(1'-(carbo-t-butoxy)-4'- propylidene-L-2 pyrrolidinecarbonyl) 7(S)chloro7- deoxy-a-thiolincosaminide is obtained as a glassy residue whichis used in the next step.

9 El.3 "-l'-demethyl-7 (S) chloro 7 deoxylincomycin hydrochloride HN AHO onion. K B

on \1 SMe on H 1L- CH;

-HCl 1 (HJ-HN- 0 H omen: K )i on SMe on A solution of 9.8 g. of methylN-(1'-carbo-t-butoxy)- 4-propylidne-L 2' pyrrolidinecarbonyl)-7(S)-chloro-7- deoxy-a-thiolincosaminide in 25 ml. of methanol and 20 ml.H O is acidified with 1.8 ml. of 6 N hydrochloric acid and warmed for 1hr. on the steam bath. The methanol is distilled in vacuo and theaqueous solution extracted with methylene chloride. The aqueous extractis acidified with 6 N HCl and extracted 3 times with 25 ml. portions ofMeCl The combined extract is dried and evaporated to give a residue of2.336 g. This is warmed with 10 ml. of acetone from which precipitates300 mg. of product as the free base, M.P. l65171 C. The acetone solublefiltrate is acidified with 6 N HCl. Crystalline hydrochloride salt, M.P.177-185" C. dec., and Weighing 1.4 g. precipitates.

This solid is crystallized from 15 ml. of acetonitrile and ml. ofmethanol to yield 1.15 g. of A -"-1'-demethyl-7(S)-chloro-7-deoxylincomycin hydrochloride, M.P. 175- 185 C. dec.

Analysis.-Calcd. for C H N O SCl-HCl (percent): C, 45.84; H, 6.79; N,6.29; S, 7.20; Cl, 15.92. Found (percent): C, 45.42; H, 7.08; N, 6.05;S, 7.09; Cl, 15.77. (Corrected for 4.16% E 0 determined by Karl Fischeranalysis.) v

By substituting the 1-carbobenzoxy-4-propylidene-L-2-pyrrolidinecarboxylic acid of Example 1 byl-carbobenzoxy-4-butylidene-L-2-pyrrolidinecarboxylic acid, 1-carbobenzoxy 4 pentylidene-L-Z-pyrrolidinecarboxylic acid,l-carbobenzoxy 4 hexylidene-L-Z-pyrrolidinecarboxylic acid,1-carbobenzoxy-4-octylidene-L-Z-pyrrolidinecarboxylic acid,1carbobenzoxy-4-cyclohexylidene-L- 2 pyrrolidinecarboxylic acid, and 1carbobenzoxy 4- benzylidene-L-2-pyrrolidinecarboxylic acid there areobtained 4-butylidene-L-Z-pyrrolidinecarboxylic acid, 4-pentylidene-L-2-pyrrolidinecarboxylic acid, 4-hexylidene-L-2-pyrrolidinecarboxylic acid, 4-octylidene-L-Z-pyrrolidinecarboxylicacid, 4-cyclohexylidene-L-2-pyrrolidinecarboxylic acid, and4-benzylidene-L-2-pyrrolidinecarboxylic acid; 1- (carbo-t-butoxy)-4-butylidene-L-2-pyrrolidinecarboxylic acid,1-(carbo-t-butoxy)-4-pentylidene-L-l-pyrrolidinecarboxylic acid,l-(carbo-t-butoxy)-4-hexylidene- L-2-pyrrolidinecarboxylic acid, 1(carbo-t-butoxy) 4- octylidene-L 2 pyrrolidinecarboxylic acid,l-(carbo-tbutoxy)-4-cyclohexylidene-L-2-pyrrolidinecarboxylic acid, and1 (carbo-t-butoxy) 4-benzylidene-L-Z-pyrrolidinecarboxylic acid; methylN-(l'-(carbo-t-butoxy)-4-butylidene-L-Z-pyrrolidinecarbonyl)-7 (S)chlOrO-7-de0xy-athiolincosaminide, methyl N-(l (carbo-t-butoxy) 4-pentylidene -L 2 pyrrolidinecarbonyl)-7(S)-chloro-7-deoxy-a-thiolincosaminide, methyl N-(1-(carbo-t-butoxy) 4'hexylidene-L-Z'-pyrrolidinecarbonyl) 7 (S)-chloro-7-deoxy-a-thiolincosaminide, methyl N-(1-(carbot-butoxy) 4octylidene-L-2'-pyrrolidinecarbonyl)-7 (S)- 10chloro-7-deoxy-a-thiolincosaminide, methyl N- 1'-(carbot-butoxy) 4cyclohexylidene-L-Z-pyrrolidinecarbonyl) 7(S) chloro 7deoxy-a-thiolincosaminide, and methylN-(1-(carbo-t-butoxy)-4-benzylidene-L-2' pyrrolidinecarbonyl)-7 (S)chloro 7 deoxy-m-thiolincosaminide; methyl N-(4'-butylidene-L-2'-pyrrolidinecarbony1) -7 (Schloro-7-deoxy-a-thiolincosaminide, methylN-(4'-pentylidene-L-Z-pyrrolidinecarbonyl) 7(S)chloro-7-deoxya-thiolincosaminide, methyl N-(4-hexylidene-L-2'-pyrrolidinecarbonyl)-7(S) chloro 7 deoxy-a-thiolincosaminide, methyl N (4'octylidene-L-2'-pyrrolidinecarbonyl)-7 (S)-chloro 7deoxy-a-thiolincosaminide, methyl N-(4'-cyclohexylidene-L-2-pyrrolidinecarbonyl) -7 (Schloro-7-deoxy-a-thiolincosaminide, and methyl N-(4'-bonzylidene-L-2'-pyrrolidinecarbonyl) 7(S) chloro 7-deoxy-a-thiolincosaminide.

By substituting the chlorine in part C-l by bromine the corresponding7(S)-bromo-7-deoxy compounds are obtained. By substituting the carbontetrachloride of part 02 by carbon tetraiodidc, the corresponding7(S)-iodo-7- dcoxy compounds are obtained.

By substituting the methyl m-thiolincosaminide of part C by ethyl andhigher alkyl a-thiolincosaminides (U.S. Pat. 3,380,992) there areobtained the corresponding ethyl and higher alkylN-(4-alkylidene-L-2'-pyrrolidinecarbonyl)-7(S)-halo-7-deoxy athiolincosaminides and the corresponding ethyl and higher alkylN-(l'-(carbo-tbutoxy)-4'-alkylidene-L-2' pyrrolidinecarbonyl)-7-(S)-7-deoxy-tz-thiolincosaminide.

By substituting the methyl a-thiolincosaminide of part C by methyl andhigher alkyl 7-epl-a-thiOlinCOSarninides (U.S. Pat. 3,380,992) there areobtained the corresponding methyl and higher alkylN-(4'-alkylidene-L-2-pyrrolidinecarbonyl)-7(R)-halo-7-deoxy a,thiolincosaminides and the correspondingN-(1'-(carbo-t-butoxy)-4-alkyliene-L-2'-pyrrolidinecarbonyl-7(R)-halo 7dEOXY-athiolincosaminides.

EXAMPLE 2 A '--7(S)-chloro-7-deoxylincomycin [methyl 7-chloro-6,7,8-trideoxy-6-(l'-methyl 4' propylidene-L-Z-pyrrolidinecarboxamido) 1thio-L-threo-u-D-galactooctopyranoside] A2.-The free base: A suspensionof 2.3 g. (0.005 mole) A ""-lincomycin hydrochloride in 50 ml. of carbontetrachloride is stirred well at 25 C. under nitrogen. 9 ml. of thionylchloride is added all at once and stirring continued for 2 hrs. Duringthis period the solid dissolves and a clear solution is obtained. Thereaction mixture is heated at reflux for 2 hrs., the heat source thenremoved and nitrogen bubbled into the amber solution until the pottemperature drops to 25$ C. About 40 ml. of liquid is removed via vacuumdistillation at a pot temperature of less than 35 C. The yellow solidwhich precipitated during this distillation is collected and dried. Thissolid is dissolved in about 3 ml. of methanol, cooled at 25 C., madebasic (pH 11) with dilute aqueous sodium hydroxide solution (2 N),diluted to about 12 ml. with water and extracted well with ether. Theether extracts are combined, washed with a small amount of water, driedover anhydrous magnesium sulfate and filtered. On evaporation of analiquot of the combined ether extract A ',-7(S)-chloro-7-deoxylincomycinfree base is obtained as a yellow amorphous solid.

B2.The hydrochloride: Addition of hydrogen chloride gas to the filtrateof part A results in the precipita- SGHs A3.A '-1-demethyl-7(S)-chlor0 7deoxylincomycin free base: A -l-demethyl-7(S)-chloro-7-deoxylincomycinhydrochloride (Part 13-1), 300 mg. is dissolved in 50 m1. of water. ThepH of the solution is adjusted to 9.4 by using an anion exchange resinin the hydroxide form. The resin is obtained by chloromethylating by theprocedure given on pages 88 and 97 of Kunin, Ion Exchange Resins, 2nded. (1958), John Wiley & Sons, Inc., polystyrene cross-linked, ifdesired, with divinylbenzene, prepared by the procedure given on page 84of Kunin, supra, and quaternizing with trimethylamine ordimethylethanolamine, by the procedure given on page 97 of Kunin, supra.The alkaline solution is then freezedried to give A-l-demethyl-7(S-)-chloro-7-deoxylincomycin free base.

B-3.A ,-1'-demethyl-1'-ethyl-7(S)-chloro- 7 deoxylincomycinhydrochloride: A "-1'-demethyl-7(S)- chloro-7-deoxylincomycin free base(part A-3) is dissolved in 20 ml. of methylene chloride and 3 n11. ofmethanol. After 3 ml. of ethyl iodide and 2 ml. of triethylamine areadded, the mixture is allowed to stand at room temperature for 2 hoursat which time 5 ml. of ethyl iodide and 3 ml. of triethylamine areadded. The reaction mixture is held at 40 C. for 3 hours, after which itis concentrated to dryness. The residue is dissolved in 30 ml. of water,the pH adjusted to 10.0 With 1 N aqueous sodium hydroxide, and thealkaline solution then extracted three times with methylene chloride.The methylene chloride extracts are concentrated to dryness and theresidue dissolved in methanolic hydrogen chloride. This solution ismixed with 3 ml. of acetone and 100 ml. of ether to precipitate A"-1-demethyl-1'-ethyl-7(S)- chloro-7-deoxylincomycin hydrochloride whichis separated by filtration and dried.

By substituting the ethyl iodide by methyl iodide there is obtained A'--7(S) chloro-7-deoxylincomycin hydrochloride identical with that ofpart B-2.

We claim: 1. A compound of the formula -Halo AeNH- llklkyl wherein R isalkylidene of not more than 20 carbon atoms (including methylene),cycloalkylidene of from 3 to not more than 8 carbon atoms, andaralkylidene of not more than 12 carbon atoms; and Alkyl contains notmore than 20 carbon atoms.

2. A compound according to claim 1 in which R contains not more than 8carbon atoms and R and Alkyl are methyl or ethyl.

3. A compound according to claim 2 in which Halo is chlorine.

4. A compound according to claim 2 in which Halo is 7(S)-chloro.

5. A compound of claim 4 in which R is propylidene.

6. .A compound of the formula -Halo where Halo is chlorine or bromine; Ris alkyl of not more than 12 carbon atoms; and R is alkylidene of notmore than 20 carbon atoms, cycloalkylidene of 3 to not more than 8carbon atoms, and aralkylidene of not more than 12 carbon atoms.

7. A compound according to claim 6 in which R contains not more than 8carbon atoms and R is methyl or ethyl.

8. A compound according to claim 7 in which Halo is chlorine.

9. A compound according to claim 7 in which Halo is 7(S)-chlor0.

10. A compound of claim 9 in which R is propylidene.

References Cited UNITED STATES PATENTS 3,418,414 12/1968 Houtman 260210R 3,555,007 1/1971 Magerlein 260210 R LEWIS GOTTS, Primary Examiner J.R. BROWN, Assistant Examiner US. 'Cl. X.R.

UNITED STATES PATENT OFFICE 5 CERTIFICATE OF CORRECTION Patent No.5,726,858 Dated April 10, 1975 Invenwfls) Robert D Bl rkenmeyer and FredKagan It is certified that error appears in the above-identified patentt rt said Letters Patent are hereby corrected as shown below:

EV." i

Column 1, l ine 65, for "695,515" read 696,515

Col umn 2, l ine 33 f r "al kyl cona ins no read Al kyl contains not--1- "Col umn 5, l lne 67, for "sol volptic read sol vol ytic Col umn 6,l ine 75', for "sol uton" read sol ution Column '8, line 10, for "L-pyrrl id ine" r'e d L-2-pyrrol ldine Col umn 9, l ine l, for read Z\ Column10', l ine 14, For "bonzylidlne" read benzyl ldine Column 10, 1 ine 61,for "25$ c." read 25 c.

Column 2, lines 21-27 should read as follows:

A l kyl 2; FOR. '3 (l 5 cp .pc 60375.;5; u.sv covinnuaylr "91mg; OFFICE:I969 O-Jis-JM UNITED STATES PA'IENT oFFicE CERTIFICATE OF CURRECTIONPatent No. 5.726,858 Dated Apr i I D 10. 1975 Inventor(s) Robert D Birkenmeyer and Fred Kagan g 2 It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 2, 1 i'nes 57-43 should read as follows: l

Column 4, l ine 11, for "V l; read I eolumn 4, l ine 39, for "(V-I Iread V I Col umn 7', 1 ines 34- 40 should read as fol lows LZHS I IC2YHSI Signed and sealed this 1st day of January 1974.

(SEAL) Attest:

EDWARD L-LPLETCHERJR, RENE D. TEGTMEYER At'testing OfficerActing-Commissionerof Patents F 5 7 uscom-pc Boas-ago UNlTED STATESPATENT OFFICE CERTIFICATE OF CORRECTION Rntent Jo. 3,726,858 Dated April10, 1973 I fl Robert D Bi rkenmeyer and Fred Kagan It is certified thaterror appears in the above-identified patent t t said Letters Patent arehereby corrected as shown below:

Column 1, line 63, for "695,513" read 696,515

Col mm 2, 1 ine 33 f r "alkyl cona ins no read A1 kyl contains not 1'Col umn 5, 1 ine 67, for so] vol ptic" read solvolytic Column 6, 1 ine73, for "soluton" read JlUtiOfl ColurnnB, l ine 10, for L-pyrr l idine"re d i 2-pyrrol id ine Col umn 9, 1 ine l for read Column 10, 1 ine 14,For bon2y1idine" read benzylidine Co.umn 10, l ine 61, For "25$ C. read25 C.

Column 2, l Ines 21-27 should read as Fol lows I? 1 kyl N OI" E-OHfi--OH R1 R 0 UNITED STATES PATENT OFFICE CERTIFICATE 0F CORRECTIONPP-Ulnt 3.726.858 Dated Apr i I 10, 1973 Inventor(s) Robert D. Bir'kenmeyer and Fred Kagan 8 2 It is certified that error appears in theabove-identified patent ad that said Letters Patent are hereby correctedas shown below:

Column 2, l ines 57-43 should read as fol lows Column l ine 11, For "2V[5 read I column l ine 39, For (V I I read VI Column 7, I ines 54- 40should read as fol lows al-l5 Q S Signed and sealed this lst day ofJanuary 1974.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. RENE D. TEGTMEYER Attesting OfficerActing-Commissioner of Patents

